The invention described herein was not made with the aid of any federally sponsored grants.
The present invention relates to compounds that modulate the PPARxcex3 receptor and are useful in the diagnosis and treatment of type II diabetes (and complications thereof), hypercholesterolemia (and related disorders associated with abnormally high or low plasma lipoprotein or triglyceride levels) and inflammatory disorders.
The peroxisome proliferator-activated receptors (PPARs) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the plelotropic effects of fatty acid peroxisome proliferators. These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid metabolism has provided insight into regulation of energy homeostasis in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia.
PPARxcex3 is one member of the nuclear receptor superfamily of ligand-activated transcription factors and has been shown to be expressed in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPARxcex3 plays a pivotal role in the adipogenic signaling cascade. PPARxcex3 also regulates the ob/leptin gene which is involved in regulating energy homeostasis, and adipocyte differentiation which has been shown to be a critical step to be targeted for anti-obesity and diabetic conditions.
In an effort to understand the role of PPARxcex3 in adipocyte differentiation, several investigators have focused on the identification of PPARxcex3 activators. One class of compounds, the thiazolidinediones, which were known to have adipogenic effects on preadipocyte and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were also demonstrated to be PPARxcex3-selective ligands. More recently, compounds that selectively activate murine PPARxcex3 were shown to possess in vivo antidiabetic activity in mice.
Despite the advances made with the thiazolidinedione class of antidiabetes agents, unacceptable side effects have limited their clinical use. Accordingly, there remains a need for potent, selective activators of PPARxcex3 which will be useful for the treatment of NIDDM and other disorders related to lipid metabolism and energy homeostasis. Still further, compounds that block PPARxcex3 activity would be useful for interfering with the maturation of preadipocytes into adipocytes and thus would be useful for the treatment of obesity and related disorders associated with undesirable adipocyte maturation. Surprisingly, the present invention provides compounds that are useful as activators as well as antagonists of PPARxcex3 activity and compositions containing them, along with methods for their use.
In one aspect, the present invention provides methods of modulating conditions which are mediated by PPARxcex3. The methods typically involve contacting the host with a PPARxcex3-modulating amount of a compound having the formula: 
in which the symbol Ar1 represents a substituted or unsubstituted aryl group; the letter X represents a divalent linkage selected from substituted or unsubstituted (C1-C6)alkylene, substituted or unsubstituted (C1-C6)alkylenoxy, substituted or unsubstituted (C1-C6)alkylenamino, substituted or unsubstituted (C1-C6)alkylene-S(O)k, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94, xe2x80x94N(R11)C(O)xe2x80x94, xe2x80x94S(O)kxe2x80x94 and a single bond, in which R11 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and aryl(C1-C4)alkyl and the subscript k is an integer of from 0 to 2. The letter Y, in the above formula represents a divalent linkage selected from substituted or unsubstituted (C1-C6)alkylene, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, N(R12)xe2x80x94S(O)mxe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94N(R13), xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, a single bond, and combinations thereof, in which R12 and R13 are members independently selected from hydrogen, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C2-C8)heteroalkyl and substituted or unsubstituted aryl(C1-C4)alkyl; and the subscripts m and n are independently integers of from 0 to 2.
The symbol R1 represents a member selected from hydrogen, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)alkoxy, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94C(O)R14, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94OR17, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17 and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94OR17, in which R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl, and aryl(C1-C4)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; and R17 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl. In each of the descriptions of, for example, alkyl, alkoxy and heteroalkyl, the groups can be substituted or unsubstituted.
The symbol R2 represents a substituted or unsubstituted aryl group. Preferably, R2 represents a phenyl, naphthyl, pyridazinyl or pyridyl group. More preferably, R2 is a phenyl, naphthyl, pyridazinyl or pyridyl group substituted with from 0-3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94(C1-C8)alkyl and xe2x80x94NH2.
The symbol R3 represents a halogen, cyano, nitro or a substituted or unsubstituted (C1-C8)alkoxy group.
In another aspect, the present invention provides compounds of the formula above, as well as pharmaceutical compositions containing the compounds described above.
Abbreviations and Definitions:
The following abbreviations are used herein: PPARxcex3: peroxisome proliferator-activated receptor xcex3; NIDDM: non-insulin-dependent diabetes mellitus; Et3N: triethylamine; MeGH: methanol; and DMSO: dimethylsulfoxide.
The term xe2x80x9calkyl,xe2x80x9d by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term xe2x80x9calkyl,xe2x80x9d unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as xe2x80x9cheteroalkyl,xe2x80x9d xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9calkylene.xe2x80x9d The term xe2x80x9calkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by xe2x80x94CH2CH2CH2CH2xe2x80x94. Typically, an alkyl group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A xe2x80x9clower alkylxe2x80x9d or xe2x80x9clower alkylenexe2x80x9d is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
The term xe2x80x9cheteroalkyl,xe2x80x9d by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94CH3, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94CH3, xe2x80x94Si(CH3)3, xe2x80x94CH2xe2x80x94CHxe2x95x90Nxe2x80x94OCH3, and xe2x80x94CHxe2x95x90CHxe2x80x94N(CH3)xe2x80x94CH3. Up to two heteroatoms may be consecutive, such as, for example, xe2x80x94CH2xe2x80x94NHxe2x80x94OCH3 and xe2x80x94CH2xe2x80x94Oxe2x80x94Si(CH3)3. Also included in the term xe2x80x9cheteroalkylxe2x80x9d are those radicals described in more detail below as xe2x80x9cheteroalkylenexe2x80x9d and xe2x80x9cheterocycloalkyl.xe2x80x9d The term xe2x80x9cheteroalkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, as well as all other linking group provided in the present invention, no orientation of the linking group is implied.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9cheterocycloalkylxe2x80x9d, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of xe2x80x9calkylxe2x80x9d and xe2x80x9cheteroalkylxe2x80x9d, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as xe2x80x9cfluoroalkyl,xe2x80x9d are meant to include monofluoroalkyl and polyfluoroalkyl.
The term xe2x80x9caryl,xe2x80x9d employed alone or in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The rings may each contain from zero to four heteroatoms selected from N, O, and 5, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The aryl groups that contain heteroatoms may be referred to as xe2x80x9cheteroarylxe2x80x9d and can be attached to the remainder of the molecule through a heteroatom Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-benzothiazolyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl, and 6-quinolinyl. Substituents for each of the above noted aryl ring systems are selected from the group of acceptable substituents described below. The term xe2x80x9carylalkylxe2x80x9d is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
Each of the above terms (e.g., xe2x80x9calkyl,xe2x80x9d xe2x80x9cheteroalkylxe2x80x9d and xe2x80x9carylxe2x80x9d) are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: xe2x80x94ORxe2x80x2, xe2x95x90O, xe2x95x90NRxe2x80x2, xe2x95x90Nxe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, -halogen, xe2x80x94SiRxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94C(O)Rxe2x80x2, xe2x80x94CO2Rxe2x80x2, CONRxe2x80x2Rxe2x80x3, xe2x80x94OC(O)NRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)NRxe2x80x3Rxe2x80x2xe2x80x3, xe2x80x94NRxe2x80x3C(O)2Rxe2x80x2, xe2x80x94NHxe2x80x94C(H2)xe2x95x90NH, xe2x80x94NRxe2x80x2C(NH2)xe2x95x90NH, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94CN and xe2x80x94NO2 in a number ranging from zero to (2N+1), where N is the total number of carbon atoms in such radical. Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 each independently refer to hydrogen, unsubstituted(C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When Rxe2x80x2 and Rxe2x80x3 are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, xe2x80x94NRxe2x80x2Rxe2x80x3 is meant to include 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term xe2x80x9calkylxe2x80x9d is meant to include groups such as haloalkyl (e.g., xe2x80x94CF3 and xe2x80x94CH2CF3) and acyl (e.g., xe2x80x94C(O)CH3, xe2x80x94C(O)CF3, xe2x80x94C(O)CH2OCH3, and the like). Preferably, the alkyl groups (and related alkoxy, heteroalkyl, etc.) are unsubstituted or have 1 to 3 substituents selected from halogen, xe2x80x94ORxe2x80x2, xe2x95x90O, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94C(O)Rxe2x80x2, xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94CN and xe2x80x94NO2. More preferably, the alkyl and related groups have 0, 1 or 2 substituents selected from halogen, xe2x80x94ORxe2x80x2, xe2x95x90O, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94CN and xe2x80x94NO2.
Similarly, substituents for the aryl groups are varied and are selected from halogen, xe2x80x94ORxe2x80x2, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94Rxe2x80x2, xe2x80x94CN, xe2x80x94NO2xe2x80x94 xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94C(O)Rxe2x80x2, xe2x80x94OC(O)NRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94NRxe2x80x3C(O)2Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)NRxe2x80x3Rxe2x80x2xe2x80x3, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NH, xe2x80x94NRxe2x80x2C(NH2)xe2x95x90NH, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94N3, xe2x80x94CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl. Preferably, the aryl groups are unsubstituted or have from 1 to 3 substituents selected from halogen, xe2x80x94ORxe2x80x2, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94Rxe2x80x2, xe2x80x94CN, xe2x80x94NO2xe2x80x94 xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94C(O)Rxe2x80x2, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl. Still more preferably, the aryl groups have 0, 1 or 2 substituents selected from halogen, xe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94Rxe2x80x2, xe2x80x94CN, xe2x80x94NO2xe2x80x94 xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl.
Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula wherein T and U are independently xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94 or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94Axe2x80x94(CH2)rxe2x80x94Bxe2x80x94, wherein A and B are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, NHxe2x80x94, xe2x80x94Sxe2x80x94, -5(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2NRxe2x80x2xe2x80x94 or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94(CH2),xe2x80x94Xxe2x80x94(CH2)txe2x80x94, where s and t are independently integers of from 0 to 3, and X is xe2x80x94Oxe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2NRxe2x80x2xe2x80x94. The substituent Rxe2x80x2 in xe2x80x94NRxe2x80x2xe2x80x94 and xe2x80x94S(O)2NRxe2x80x2xe2x80x94 is selected from hydrogen or unsubstituted (C1-C6)alkyl.
As used herein, the term xe2x80x9cheteroatomxe2x80x9d is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., xe2x80x9cPharmaceutical Saltsxe2x80x9d, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
General:
A new class of compounds that interact with PPARxcex3 has now been discovered. Depending on the biological environment (e.g., cell type, pathological condition of the host, etc.), these compounds can activate or block the actions of PPARxcex3. By activating the PPARxcex3 receptor, the compounds will find use as therapeutic agents capable of modulating conditions mediated by the PPARxcex3 receptor. As noted above, example of such conditions is NIDDM. Additionally, the compounds are useful for the prevention and treatment of complications of diabetes (e.g., neuropathy, retinopathy, glomerulosclerosis, and cardiovascular disorders), and treating hyperlipidemia. Still further, the compounds are useful for the modulation of inflammatory conditions which most recently have been found to be controlled by PPARxcex3 (see, Ricote, et al., Nature, 391:79-82 (1998) and Jiang, et al., Nature, 391:82-86 (1998). Examples of inflammatory conditions include rheumatoid arthritis and atherosclerosis.
Compounds that act via antagonism of PPARxcex3 are useful for treating obesity, hypertension, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, and metabolic disorders.
Embodiments of the Invention:
In one aspect, the present invention provides compounds which are represented by the formula: 
In formula (I), the symbol Ar1 represents a substituted or unsubstituted aryl group. Preferably, Ar1 is a monocyclic or fused bicyclic aryl group having from zero to four heteroatoms as ring members. More preferably, Ar1 is a monocyclic or fused bicyclic aryl group comprising two fused six-membered rings, two fused five-membered rings, or a six-member ring having a fused five-membered ring. heteroaryl group containing from 1 to 3 nitrogen atoms in the ring or rings. Particularly preferred embodiments are those in which Ar1 is phenyl, naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, and benzimidazolyl, with the proviso that when Ar1 is substituted or unsubstituted 2-benzothiazolyl, then X is xe2x80x94S(O)kxe2x80x94 wherein the subscript k is 0, 1 or 2. As noted above, Ar1 can be both unsubstituted and substituted. In preferred embodiments, Ar1 is substituted with from 0 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94CF3, (C1-C6)alkyl, or xe2x80x94NO2. In one group of preferred embodiments, Ar1 is a monocyclic heteroaryl group containing 1 to 2 nitrogen atoms in the ring and being monosubstituted by halogen, xe2x80x94OCF3 or xe2x80x94CF3. In another group of preferred embodiments, Ar1 is a phenyl or naphthyl group having from 1 to 3 substituents selected from halogen, cyano, nitro, (C1-C8)alkyl or (C1-C8)alkoxy.
The letter X represents a divalent linkage selected from substituted or unsubstituted (C1-C6)alkylene, substituted or unsubstituted (C1-C6)alkylenoxy, substituted or unsubstituted (C1-C6)alkylenamino, substituted or unsubstituted (C1-C6)alkylene-S(O)k, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94, xe2x80x94N(R11)C(O)xe2x80x94, xe2x80x94S(O)kxe2x80x94 and a single bond, in which R11 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and aryl(C1-C4)alkyl and the subscript k is an integer of from 0 to 2. In preferred embodiments, X represents xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, substituted or unsubstituted (C1-C6)alkylene, xe2x80x94N(R11)xe2x80x94, or xe2x80x94S(O)kxe2x80x94. Most preferably, X represents xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(CH2CH3)xe2x80x94, xe2x80x94CH(isopropyl)-, xe2x80x94CH(CN)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94, or xe2x80x94S(O)kxe2x80x94. Still further preferred are those embodiments in which X represents xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94, or xe2x80x94S(O)kxe2x80x94, wherein R11 is hydrogen, methyl, ethyl, propyl and isopropyl.
The letter Y, in the above formula represents a divalent linkage selected from substituted or unsubstituted (C1-C6)alkylene, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94N(R13)xe2x80x94, xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, a single bond, and combinations thereof, in which R12 and R13 are members independently selected from hydrogen, substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C2-C8)heteroalkyl and substituted or unsubstituted aryl(C1-C4)alkyl; and the subscripts m and n are independently integers of from 0 to 2. In preferred embodiments, Y represents xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R12)xe2x80x94C(O)xe2x80x94. More preferably, Y represents xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94 in which R12 is hydrogen or substituted or unsubstituted (C1-C8)alkyl. Most preferably, Y represents xe2x80x94NHxe2x80x94S(O)2xe2x80x94. Additionally, the linkages provided herein (represented by X and Y) can be in either orientation. More particularly, for example, the nitrogen atom of xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94 can be attached to either the central benzene ring or to the R2 group.
The symbol R1 represents a member selected from hydrogen, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)alkoxy, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94C(O)R14, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94OR17, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17 and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94OR17, in which R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl, and aryl(C1-C4)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; and R17 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl. In each of the descriptions of, for example, alkyl, alkoxy and heteroalkyl, the groups can be substituted or unsubstituted. Preferably, when substituted the substituents are halogen (e.g., xe2x80x94CF3, xe2x80x94OCF3). In preferred embodiments, R1 represents hydrogen, halogen, cyano, (C1-C8)alkyl, (C1-C8)alkoxy, xe2x80x94CO2R14 and xe2x80x94C(O)NR15R16. More preferably, R1 represents hydrogen, halogen, cyano, (C1-C8)alkyl, (C1-C8)alkoxy, xe2x80x94CO2R14 and xe2x80x94C(O)NR15R16 in which R14 is (C1-C8)alkyl, and R15 and R16 are independently hydrogen or (C1-C8)alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring. Other preferred R1 groups are discussed below with reference to groupings of compounds wherein Ar1 is phenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl.
The symbol R2 represents a substituted or unsubstituted aryl group. Preferably, R2 represents a phenyl, naphthyl, pyridazinyl or pyridyl group. More preferably, R2 is a phenyl, naphthyl, pyridazinyl or pyridyl group substituted with from 0-3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94(C1-C8)alkyl and xe2x80x94NH2. While certain preferred substituents have been provided (e.g., xe2x80x94OCF3 and xe2x80x94CF3), the terms alkyl and alkoxy are also meant to include substituted versions thereof, preferably halosubstituted versions including those specifically noted.
The symbol R3 represents a halogen, cyano, nitro or a substituted or unsubstituted (C1-C8)alkoxy group, preferably a halogen, cyano or (C1-C4)alkoxy group. Most preferably, halogen, methoxy or trifluoromethoxy.
A number of preferred embodiments are provided herein. For example, in one preferred embodiment, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94; and Y is xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl. In another preferred embodiment, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94; Y is xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; and R2 is a substituted or unsubstituted aryl selected from phenyl, pyridyl, naphthyl and pyridazinyl. In yet another preferred embodiment, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94; Y is xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R2 is a substituted or unsubstituted aryl selected from phenyl, pyridyl, naphthyl and pyridazinyl; and Ar1 is a substituted or unsubstituted aryl selected from pyridyl, phenyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, and benzimidazolyl.
One of skill in the art will understand that a number of structural isomers are represented by formula I. In one group of embodiments, the isomers are those in which the groups on the phenyl ring occupy positions that are not contiguous. In other embodiments, the compounds are those having the structural orientations represented by the formulae: 
Still further preferred are those compounds having the structural orientation represented by formula Ia or Ib. Still other preferred compounds, are those of formula Ia or Ib in which the positions of R1 and R3 are switched (or reversed).
Yet other preferred compounds are those in which Ar1xe2x80x94Xxe2x80x94 and xe2x80x94Yxe2x80x94R2 occupy positions ortho to one another (exemplified by Ij). 
Still another group of preferred compounds are represented by the formula: 
Ar1 is Substituted or Unsubstituted Phenyl
In one group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted phenyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted phenyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is a phenyl group having from 1 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is a member selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3.
Ar1 is Substituted or Unsubstituted Pyridyl
In one group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted pyridyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted pyridyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8) alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is a pyridyl group having from 0 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is a member selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3. Most preferably, Ar1 is a 3-pyridyl group having preferred substituents as indicated above.
In still other particularly preferred embodiments, the compounds are represented by formula I, in which Ar1 is a pyridyl ring having a single substituent selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; X is a divalent linkage selected from the group of xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94CH2xe2x80x94 and combinations thereof; Y is a divalent linkage selected from the group of xe2x80x94NHxe2x80x94S(O)2xe2x80x94 and xe2x80x94NHxe2x80x94C(O)xe2x80x94; R1 is selected from hydrogen, halogen, cyano, (C1-C8)alkyl, (C1-C8)alkoxy and xe2x80x94C(O)NR15R16 in which R15 and are selected from hydrogen, (C1-C8)alkyl, aryl and aryl(C1-C4)alkyl; R2 is a phenyl or pyridyl ring, optionally substituted by 0-3 groups selected from halogen, (C1-C8)alkyl, xe2x80x94Oxe2x80x94(C1-C8)alkyl and xe2x80x94CN; and R3 is halogen, cyano or (C1-C4)alkoxy.
Ar1 is Substituted or Unsubstituted Naphthyl
In one group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted naphthyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted naphthyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is a naphthyl group having from 0 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is a member selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3.
Ar1 is Substituted or Unsubstituted Benzothiazolyl
In another group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted benzothiazolyl group, with the proviso that when Ar1 is substituted or unsubstituted 2-benzothiazolyl, then X is xe2x80x94S(O)kxe2x80x94. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted benzothiazolyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is a benzothiazolyl group having from 1 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3. In particularly preferred embodiments, the benzothiazolyl group is a 2-benzothiazolyl group.
Ar1 is Substituted or Unsubstituted Benzoxazolyl
In another group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted benzoxazolyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still farther preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted benzoxazolyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is a benzoxazolyl group having from 0 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3. In particularly preferred embodiments, the benzoxazolyl group is a 2-benzoxazolyl group.
Ar1 is Substituted or Unsubstituted Benzimidazolyl
In another group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted benzimidazolyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted benzimidazolyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is a benzimidazolyl group having from 0 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3. In particularly preferred embodiments, the benzimidazolyl group is a 2-benzimidazolyl group.
Ar1 is Substituted or Unsubstituted Quinolinyl or Isoquinolinyl
In another group of particularly preferred embodiments, Ar1 is a substituted or unsubstituted isoquinolinyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar1 is substituted or unsubstituted isoquinolinyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94 and xe2x80x94Sxe2x80x94, wherein R11 is a member selected from hydrogen and (C1-C8)alkyl; Y is a divalent linkage selected from xe2x80x94N(R12)xe2x80x94S(O)2xe2x80x94, wherein R12 is a member selected from hydrogen and (C1-C8)alkyl; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17, wherein R14 is a member selected from hydrogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl; R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring; R17 is a member selected from hydrogen, (C1-C8)alkyl and (C2-C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C1-C8)alkoxy.
In further preferred embodiments, X is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94; Y is xe2x80x94NHxe2x80x94SO2xe2x80x94; R1 is a member selected from hydrogen, halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14 and xe2x80x94S(O)qxe2x80x94NR15R16; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2; and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar1 is an isoquinolinyl group having from 0 to 3 substituents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C6)alkyl, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NO2; R1 is selected from halogen, (C1-C8)alkyl, (C2-C8)heteroalkyl and (C1-C8)alkoxy; R2 is a phenyl group having from 0 to 3 substitutents selected from halogen, xe2x80x94OCF3, xe2x80x94OH, xe2x80x94O(C1-C8)alkyl, xe2x80x94C(O)xe2x80x94(C1-C8)alkyl, xe2x80x94CN, xe2x80x94CF3, (C1-C8)alkyl and xe2x80x94NH2, more preferably 1 to 3 substituents selected from halogen, xe2x80x94OCF3 and xe2x80x94CF3; and R3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R1 and R3 are each independently a halogen, and R2 is a phenyl group having from 1 to 3 substitutents selected from halogen, xe2x80x94OCF3, and xe2x80x94CF3. In particularly preferred embodiments, the isoquinolinyl group is selected from 3-isoquinolinyl and 4-isoquinolinyl groups.
In another aspect, the present invention provides pharmaceutical compositions comprising at least one of the above compounds in admixture with a pharmaceutically acceptable excipient.
In yet another aspect, the present invention provides methods for modulating conditions mediated by PPARxcex3 in a host. More particularly, the conditions are selected from non-insulin-dependent diabetes mellitus, obesity, conditions associated with abnormal plasma levels of lipoproteins or triglycerides, and inflammatory conditions such as, for example, rheumatoid arthritis and atherosclerosis.
Preparation of the Compounds
The compounds of the present invention can be prepared using standard synthetic methods. For exemplary purposes, Scheme 1 illustrates methods for the preparation of compounds of structural formula (Ia). One of skill in the art will understand that similar methods can be used for the synthesis of compounds in the other structural classes.
As shown in Scheme 1, compounds of the present invention can be prepared beginning with commercially available 2-chloro-5-nitrobenzonitrile (i). Treatment of J with a phenol, thiophenol, or optionally protected aniline in the presence of base and heat provides the adduct (ii). Reduction of the nitro group in ii with, for example, H2 in the presence of Raney nickel catalyst provides an aniline derivative (iii). Sulfonylation of iii with an appropriate arylsulfonyl halide (Ar1502C1) in the presence of base (typically a tertiary amine) provides a target compound (iv). Compound iii can also be converted to a related compound of formula (vi) in which the orientation of the sulfonamide linkage is reversed. Thus, conversion of the aniline iii to the benzenesulfonyl chloride v can be accomplished using methods described in Hoffman, Organic Syntheses Collective Volume VII, p. 508-511. Subsequent treatment of v with an appropriate aniline provides the target compound vi. 
Other compounds of the present invention can be prepared beginning with, for example, 3,4-difluoronitrobenzene, 3-chloro-4-fluoronitrobenzene, 2-chloro-5-nitroanisole, 3-bromo-4-fluoronitrobenzene and the like.
Analysis of the Compounds
The compounds of the present invention can be evaluated for modulation of the PPARxcex3 receptor using assays such as those described in Jiang, et al., Nature 391:82-86 (1998), Ricote, et al., Nature 391:79-82 (1998) and Lehmann, et al., J. Biol. Chem. 270(12): 12953-12956 (1995). Alternatively, the compounds can be evaluated for their ability to displace radiolabeled BRL 49653 from a PPARxcex3-GST fusion protein as follows:
Materials:
PPARxcex3-GST fusion protein (prepared according to standard procedures), [3H]-BRL 49653 having 50 Ci/mmol specific activity, Polyfiltronics Unifilter 350 filtration plate and glutathione-Sepharose(copyright) beads (from Pharmacia: washed twice with 10xc3x97binding buffer in which BSA and DTI can be left out).
Method:
Binding buffer (10 mM Tris-HCl, pH 8.0, 50 mM KCI, 10 mM DTT, 0.02% BSA and 0.01% NP-40) is added in 80 microliter amounts to the wells of the filtration plate. The test compound is then added in 10 microliters of DMSO. The PPARxcex3-GST fusion protein and radiolabeled BRL compound are premixed in binding buffer containing 10 mM DTT and added in 10 microliter amounts to the wells of the plate to provide final concentrations of 1 xcexcg/well of PPARxcex3-GST fusion protein and 10 nM [3H]-BRL 49653 compound. The plate is incubated for 15 minutes. Glutathione-agarose bead is added in 50 xcexcL of binding buffer, and the plate is vigorously shaken for one hour. The plate is washed four times with 200 xcexcL/well of binding buffer (without BSA and DTT). The bottom of the plate is sealed and 200 xcexcL/well of scintillation cocktail is added. The top of the plate is then sealed and the radioactivity is determined.
Formulation and Administration of the Compounds (Compositions)
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I).
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use for the treatment of obesity, NIDDM, or inflammatory conditions, the compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. A daily dose range of about 0.1 mg/kg to about 10 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.